tbuckley/cabot-search huggingface dataset:
Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in oesophageal adenocarcinoma
Authors: Lei Chen, Heng Lu, Dunfa Peng, Long Long Cao, Farah Ballout, Kannappan Srirmajayam, Zheng Chen, Ajaz Bhat, Timothy C Wang, Anthony Capobianco, Jianwen Que, Oliver Gene McDonald, Alexander Zaika, Shutian Zhang, Wael El-Rifai
Journal: Gut (2022)

Objective Oesophageal adenocarcinoma (EAC) arises in the setting of Barrett’s oesophagus, an intestinal metaplastic precursor lesion that can develop in patients with chronic GERD. Here, we investigated the role of acidic bile salts, the mimicry of reflux, in activation of NOTCH signaling in EAC. Design This study used public databases, EAC cell line models, L2-IL1β transgenic mouse model and human EAC tissue samples to identify mechanisms of NOTCH activation under reflux conditions. Results Analysis of public databases demonstrated significant upregulation of NOTCH signaling components in EAC. In vitro studies demonstrated nuclear accumulation of active NOTCH1 cleaved fragment (NOTCH intracellular domain) and upregulation of NOTCH targets in EAC cells in response to reflux conditions. Additional investigations identified DLL1 as the predominant ligand contributing to NOTCH1 activation under reflux conditions. We discovered a novel crosstalk between APE1 redox function, reflux-induced inflammation and DLL1 upregulation where NF-κB can directly bind to and induce the expression of DLL1. The APE1 redox function was crucial for activation of the APE1-NF-κB-NOTCH axis and promoting cancer cell stem-like properties in response to reflux conditions. Overexpression of APE1 and DLL1 was detected in gastro-oesophageal junctions of the L2-IL1ß transgenic mouse model and human EAC tissue microarrays. DLL1 high levels were associated with poor overall survival in patients with EAC. Conclusion These findings underscore a unique mechanism that links redox balance, inflammation and embryonic development (NOTCH) into a common pro-tumorigenic pathway that is intrinsic to EAC cells.
PB1873: EFFECTS OF LENALIDOMIDE MAINTENANCE IN CHRONIC LYMPHOCYTIC LEUKEMIA: A TRIAL-SEQUENTIAL ANALYSIS
Authors: C.-H. Lee, C.-L. Ho
Journal: HemaSphere (2022)

Background: Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disease in adults. Despite durable responses to front-line therapy and sustained remission rates in patients with CLL, CLL is still incurable within standard therapy and relapse eventually. Although kinase inhibitors can improve outcomes for some patients with relapsed and refractory disease, not all patients have access to these novel drugs. Maintenance therapies aim to reach a deep remission and extend the period of disease quiescence. However, the efficacy and safety of lenalidomide as a maintenance therapy are inconsistent within individual studies and still under debate. Aims: To assess the effect and safety of lenalidomide maintenance in patients with chronic lymphocytic leukemia. Methods: Eligible randomized controlled trials published before January 2022 were retrieved from databases. Primary outcomes were progression free survival (PFS) and overall survival (OS). Trial sequential analysis was adopting to examine the power of analyses in primary outcomes. Secondary outcomes were grade 3-4 neutropenia, treatment discontinuation (TD), serious adverse events (SAE) and fatal adverse events (FAE). We calculated the hazard ratio (HR) and odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four articles, involving 1,118 patients, met the selection criteria. Compared to observation, lenalidomide maintenance was associated with a statistically significant effect in prolongation of PFS (HR, 0.43; 95% CI, 0.28–0.68; I2 = 57%), and TSA confirmed the statistical power. Compared to observation, lenalidomide maintenance was no difference in OS (HR, 0.62; 95% CI, 0.29–1.30; I2 = 52%), and TSA showed that the analysis would be inconclusive. In secondary outcomes, compared to observation, lenalidomide maintenance was associated with a higher proportion of SAE (OR 4.64; 95% CI 2.96–7.26; I2 = 0%). There was no significant difference between lenalidomide maintenance therapy and observation with regard to grade 3-4 neutropenia (OR 2.30; 95% CI 0.84–6.28; I2 = 81%), TD (OR 0.76; 95% CI 0.29–1.99; I2 = 84%), and FAE (OR 0.86; 95% CI 0.28–2.63; I2 = 0%). Image:Summary/Conclusion: In our meta-analysis, lenalidomide maintenance therapy could be an effective treatment option for patients with CLL in prolongation PFS and relatively acceptable in safety concerns. Further studies would be warrant to justify the conclusion of OS.
PB2063: CHARACTERISTICS AND THERAPEUTIC RESULTS OF PATIENTS WITH REFRACTORY/RELAPSED HODGKIN LYMPHOMA IN A TUNISIAN CENTER
Authors: F. Kammoun, F. Kallel, M. Charfi, I. Ben Amor, N. Toumi, H. Ben Salah, L. Torjemane, D. Baloumi, I. Frikha, L. Khalifa, Y. Fakhfakh, O. Kassar, M. Medhafar, A. Khanfir, J. Daoued, T. Ben Othman, S. Hadiji, M. Elloumi
Journal: HemaSphere (2022)

Background: Hodgkin lymphoma (HL) is a hematologic malignancy with a high rate of curability. However, 5 to 20% are primary refractory to treatment or relapse after achieving a complete remission (CR) and present a therapeutic challenge. Aims: Our study aims to evaluate the clinical characteristics, treatment patterns, as well as therapeutic results in patients with refractory/ relapsed HL (R/R HL) in a Tunisian center. Methods: It is a retrospective study about adult patients (<60 years old) with R/R HL, treated between January 2008 and Mars 2020 at the hematology, oncology, and radiotherapy departments of the hospital of Sfax, Tunisia. The first-line treatment was based on ABVD in favorable early stages and BEACOPP regimens in advanced stages and localized stages with a bulky mediastinal mass. The standard of care for R/R HL was salvage chemotherapy followed by autologous stem cell transplantation (ASCT) in the national bone marrow transplant center in Tunis. The date of the point is in July 2021. Results: A total of 55 patients were enrolled, which represents 25% of our series of HL managed in this period. The median age was 30 years (range 17-59), and the sex ratio was 1.3. Twenty-five patients (45%) presented with refractory disease. Among the 30 patients (55%) who relapsed, 19 patients (63%) relapsed within 12 months after achieving CR. At relapse, advanced stage, anemia, and B-symptoms were respectively recorded in 60%, 33%, and 53% of cases. Two patients died before salvage chemotherapy (CT), so 53 patients were treated. Second-line CT regimens used were Cytarabine-based regimens (DHAC/DHAP) in 74% of cases, Gemcitabine-based regimens (IGEV) in 19%, and ICE in 7% of cases respectively. IGEV was the most effective regimen to mobilize peripheral blood stem cells (69% vs 30% with Cytarabine-based regimens). A CR was noted in 61% of cases. Radiotherapy was associated with CT in 35% of cases. Only 13 patients (42% of eligible patients) benefited from ASCT. The 5-year overall survival estimate for all patients was 46%, and 5-year PFS was 41%. Chemoresistance to salvage therapy, ≥ 2 lines of salvage therapy, non-realization of ASCT, and insufficient response after treatment were predictive adverse prognostic factors (p<0.001). Summary/Conclusion: Our study showed that CR and feasibility of ASCT were lower than that reported in international studies (61% vs 76%, and 46% vs 69 to 100% respectively), which incites us to a better involvement of ASCT. Besides, the association of new therapeutic agents such as Brentuximab Vedotin should be considered in our patients with chemoresistant HL.
P1627: EXPERIENCE OF THE USE OF CONVALESCENT PLASMA FOR THE MANAGEMENT OF COVID 19 IN PATIENTS WHO REQUIRED HOSPITALIZATION IN QUITO-ECUADOR, HOSPITAL METROPOLITANO, DURING THE 2020 PERIOD
Authors: J. Rojas, H. Jaramillo, F. Avalos, P. Velasco
Journal: HemaSphere (2022)

Background: Convalescent plasma as a therapeutic alternative in COVID-19 could provide passive immunity creating neutralizing antibodies, potentially decreasing viral entry into host cells; however, the exact mechanism of viral elimination in COVID 19 is not yet known and the clinical data are not conclusive. Ecuador is a low-income country so access to Tocilizumab was delayed, that is why the goverment approved the use of convalescent plasma on april 2020 as an alternative of therapy specially with critically ill patients. Aims: Describe our experiencua of the use of convalescent plasma for the management of COVID-19 in patients who required hospitalization in Hospital Metropolitano in Quito-Ecuador. Methods: This is a retrospective, descriptive study based on patients data diagnosed with COVID- 19 in Quito-Ecuador in Hospital Metropolitano who required general hospitalization and/or intensive care unit; each of them received convalescent plasma from patients with previous infection. Sociodemographic characteristics, use of plasma in general hospitalization and intensive care unit, adverse effects and mortality were included in the analysis. Results: During april 15th and december 31st 2020, 60 patients received convalescent plasma. 42 of them were male and 18 females, with an age range between 30-65 years old. Just 5 of them died during hospitalization. At the time they received plasma, 25% of the patients (15) were anticoagulated and half of them were D-dimer positive. In relation to the PAFI (ratio of arterial oxygen pressure/inspired fraction of oxygen), the ranges vary with minimum values of 70 and maximum 240, with an average of 187 millimeters of mercury. 17 patients received plasma during their stay in the Intensive Care Unit (ICU), and the remaining 43 approximately on their third day of general hospitalization. Finally, 40% presented severity criteria at the time of receiving plasma, these criteria correspond to lymphopenia less than 800 K/uL, C reactive protein (CRP) more than 100 mg/L and ferritin greater than 500 ng/ml. Image:Summary/Conclusion: The use of convalescent plasma does not allow us to demonstrate it as a curative therapy and not even show a decrease in severity in patients. It is no posible to prove the efficacy of this therapy, but we can conclude with our data, that there is a safe alternative with no transfusions reactions, and a death rate of 12%. Randomized trial data are still needed to optimize the convalescent plasma indications.
Developing guidelines for ultrarare rheumatic disorders: a bumpy ride
Authors: David Piskin, Micol Romano, Daniel Aletaha, Brian M Feldman, Raphaela Goldbach-Mansky, Loreto Carmona, Erkan Demirkaya
Journal: Annals of the Rheumatic Diseases (2022)

Clinical practice guidelines are useful tools for both patients and physicians. Several standardised operating procedures are in existence to describe tasks step by step to develop guidelines/recommendations. The end product consists of data synthesis from the systematic literature search and patient/physician’s inputs. For the prevalent diseases, the process for developing guidelines is straightforward; it is based on physicians’/patients’ experiences and abundance of the literature. When it comes to the realm of ultrarare diseases, there are few physicians who are familiar with a disease, and there is a scarcity of literature. In this viewpoint, we describe challenges from the methodological perspectives that occurred during the process of developing recommendations for autoinflammatory disorders with the goal of finding solutions that facilitate the development of guidelines for ultrarare diseases in the future.
Founder of America’s Frontline Doctors is sentenced to prison for role in Capitol riot
Authors: Owen Dyer
Journal: BMJ (2022)

<h3>Objective.</h3> The probability of achieving Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) treatment targets (remission [REM], low disease activity [LDA]) was evaluated following apremilast monotherapy in disease-modifying antirheumatic drug (DMARD)-naïve patients with psoriatic arthritis (PsA) based on baseline disease activity. <h3>Methods.</h3> This post hoc probability analysis of PALACE 4, a phase III, multicenter, randomized, placebo-controlled study, evaluated shifting across cDAPSA categories from baseline to week 52 and included DMARD-naïve patients receiving apremilast 30 mg BID with available baseline cDAPSA data. Changes in articular/extraarticular manifestations were evaluated in patients with week 52 cDAPSA components. cDAPSA treatment target achievement was assessed in a subgroup with baseline extraarticular PsA manifestations (skin involvement, enthesitis, dactylitis). <h3>Results.</h3> Of 175 apremilast-treated patients in the probability analysis, 66.3% were in high disease activity (HDA) and 31.4% in moderate disease activity (ModDA) at baseline. Approximately twice as many patients in ModDA at baseline reached REM/LDA at week 52 vs those in HDA (61.7% vs 28.2%). Achieving cDAPSA treatment targets was associated with reductions in articular (swollen/tender joints) and extraarticular (skin involvement, enthesitis, dactylitis, functional disability) disease activity. Similar treatment target achievement rates were observed in the subgroup with ≥ 1 extraarticular PsA manifestation (n = 126; ModDA: 66.7%, HDA: 32.2%). <h3>Conclusion.</h3> Apremilast-treated patients with baseline ModDA had higher probability of achieving cDAPSA treatment targets than patients with HDA. Resolution and/or near resolution of articular and/or extraarticular PsA manifestations was achieved by patients in REM/LDA at week 52. Consistent treatment target achievement was observed in patients with 1 or multiple extraarticular manifestations of active PsA.
Abstract LB203: Assessment of the safety, pharmacokinetics, and pharmacodynamics of a first-in-class cancer drug candidate E-602, a sialoglycan degrader, in non-human primates
Authors: Lizhi Cao, Jenny Che, Ali Chesney, Rakesh Dixit, Nancy Zheng, Nicole Zane, James Broderick, Li Peng
Journal: Cancer Research (2022)

Abstract E-602 is a novel, first-in-class, engineered human sialidase (Neu2) Fc fusion developed for cancer treatment by enhancing antitumor immunity through desialylating immunosuppressive sialoglycans. We have previously shown that E-602 cleaves off terminal sialic acids from surface sialoglycans on tumor and immune cells, restores the immune function of exhausted-like T cells, and enhances dendritic cell priming and activation of naïve T cells. E-602 has also demonstrated antitumor activity as a single agent in multiple syngeneic mouse tumor models. To support clinical development, we conducted a Good Laboratory Practice one-month repeat-dose toxicity study to evaluate E-602’s pharmacokinetic (PK) parameters, pharmacodynamic (PD) effects, and safety profiles in cynomolgus monkeys via weekly intravenous infusion of E-602 at 5, 30, 100, and 200 mg/kg for five doses. E-602 showed an apparent half-life (t1/2) of 4-6 hours and the terminal t1/2 of 10-30 hours with dose linearity from 30 mg/kg to 200 mg/kg. E-602 produced dose-dependent PD effects of desialylation of immune cells, such as T cells, monocytes, and dendritic cells, as monitored by flow cytometry. Despite the short half-life of E-602, the PD effect of immune cell desialylation sustained up to seven days for T cells, consistent with E-602’s enzymatic mechanism of action. Generally, E-602 was well tolerated up to 100 mg/kg with no dose-limiting adverse E-602-related changes in body weight, ophthalmology, neurological/musculoskeletal assessments, electrocardiogram parameters, respiratory rate, coagulation, urinalysis, organ weights, and histopathology. Animals in the 200 mg/kg dose group survived but showed isolated adverse histopathological changes with an uncertain relationship to E-602 administration. Therefore, the no-observed-adverse-effect-level (NOAEL) of E-602 was determined as 100 mg/kg in cynomolgus monkeys. In conclusion, the PK and PD data have supported the selection of cynomolgus monkeys as the toxicity species to evaluate E-602’s safety profile. E-602 has demonstrated sustained PD effects of immune cell desialylation up to seven days postdose and a wide safety margin with NOAEL of 100 mg/kg in cynomolgus monkeys. Citation Format: Lizhi Cao, Jenny Che, Ali Chesney, Rakesh Dixit, Nancy Zheng, Nicole Zane, James Broderick, Li Peng. Assessment of the safety, pharmacokinetics, and pharmacodynamics of a first-in-class cancer drug candidate E-602, a sialoglycan degrader, in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB203.
PB1853: IN-HOSPITAL SURVIVAL OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND CONCOMITANT CORONAVIRUS INFECTION DEPENDING ON VARIOUS CLINICAL FACTORS.
Authors: E. Baryakh, E. Misyurina, E. Zhelnova, K. Yatskov, O. Kochneva, Y. Polyakov, D. Ivanova, K. Kaluzhskaya, T. Tolstykh, T. Chudnova, I. Samsonova, M. Lysenko
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is characterized by rapid progression and requires highly intensive therapy. Complete remission is achieved in 60 to 80% of young patients. The disease can be cured in only 1/3 of patients who have achieved remission. Many patients die from infectious complications at different stages of treatment. COVID19 infection significantly worsens the prognosis of AML patients who are not in remission. Aims: To assess overall in-hospital survival of AML patients and concomitant coronavirus infection, as well as to assess survival taking into account various clinical factors. Methods: From April 2020 to August 2021, 102 AML patients aged 18-91 years: 44 men and 58 women, average age 58 years underwent treatment for coronavirus infection in the Department of Hematology of Municipal Clinical Hospital No. 52. In several cases, coronavirus infection developed during a course of chemotherapy or in the periods between the treatment courses, and therefore these patients were transported to the department via Emergency Medical Services (EMS) from other medical facilities. We assessed overall survival, as well as survival depending on age, disease status, the extent of lung damage based on the computed tomography (CT) results, neutrophil level at admission, chemotherapy performed before the onset of coronavirus infection, and at its outcome. Results: Overall survival was 44.1%. The highest mortality was in the groups of patients over 65 years of age (73.7%) with newly diagnosed disease (72.4%), with the highest extent (grade 4) of lung damage based on CT results at admission (100%). The death rate among patients with agranulocytosis at admission was 2-fold higher than among patients without agranulocytosis (66% versus 33%). The most unfavorable prognosis was found in the group of patients who received low-dose Cytosar (LDC) before the development of coronavirus infection (63.6%). Among the patients on chemotherapy at the outcome of coronavirus infection, the highest mortality was observed with LDC and hydroxyurea therapy (77.8% and 87.5%, respectively). The prognosis in these groups was probably influenced by the predominantly elderly age of patients (over 60 years), and the aggressive course of the viral infection. Summary/Conclusion: Coronavirus infection is a significant adverse factor in elderly patients with newly diagnosed AML.
PB1976: CRISPR-CAS9 KNOCKOUT SCREEN IDENTIFIES RNA MODIFICATION ENZYMES ESSENTIAL FOR CELL SURVIVAL IN MULTIPLE MYELOMA
Authors: D. Zhao, C. Pauli, C. Rohde, M. Kienhöfer, A. L. Grab, S. Huhn, M. Raab, N. Weinhold, M. Frye, C. Müller-Tidow
Journal: HemaSphere (2022)

Background: RNA modifications play a critical role in regulating gene expression and determining cell fate. Evidence is emerging that dysregulation of RNA modification pathways is involved in the development of cancer. However, the function of RNA modifying enzyems in multiple myeloma (MM) and its mechanisms are largely unknown. Aims: To identify RNA modification enzymes essential for cell survival and proliferation in myeloma. Methods: For functional analysis, we performed a focused CRISPR knock-out screen to identify RNA modifying enzymes essential for cell survival and proliferation in two myeloma cell lines, OPM2 and RPMI8226. We used a CRISPR-Cas9 library consisting of 1700 sgRNAs (~8 sgRNAs/gene) targeting around 150 RNA modifying enzymes and collected samples at day 1, 8 and 21. MAGeCK software was used to analyze the results. Results: The focused CRISPR/Cas9-screening identified six writers/erasers/readers of RNA modifications that were essential for myeloma cell survival. Among these hits, gRNAs directed against either TRMT112, YRDC, MEPCE, RBM15, EIF2 and ALKBH5 consistently inhibited cell growth. Summary/Conclusion: Several of the enzymes regulating these RNA modifications are essential for myeloma cell lines.
PB1984: ELOTUZUMAB PLUS LENALIDOMIDE AND DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA: EXTENDED 3-YEAR FOLLOW-UP OF AN ITALIAN, MULTICENTER, EXPERIENCE OUTSIDE OF CONTROLLED CLINICAL TRIALS
Authors: A. Bruzzese, D. Derudas, M. Galli, E. A. Martino, S. Rocco, C. Conticello, C. Califano, N. Giuliani, S. Mangicavalli, G. Farina, A. Lombardo, M. Brunori, E. Rossi, E. Antonioli, R. Ria, R. Zambello, N. Di Renzo, G. Mele, G. Marcacci, G. Pietrantuono, G. Palumbo, N. Cascavilla, C. Cerchione, A. Belotti, C. Criscuolo, G. Uccello, P. Curci, E. Vigna, F. Mendicino, E. Iaccino, S. Mimmi, C. Botta, D. Vincelli, N. Sgherza, A. Bonalumi, L. Cupelli, R. Stocchi, M. Martino, S. Ballanti, D. Gangemi, A. Gagliardi, B. Gamberi, A. Pompa, G. Tripepi, F. Frigeri, U. Consoli, S. Bringhen, E. Zamagni, F. Patriarca, V. De Stefano, F. Di Raimondo, S. Palmieri, M. T. Petrucci, M. Offidani, P. Musto, M. Boccadoro, M. Cavo, A. Neri, F. Morabito, M. Gentile
Journal: HemaSphere (2022)

Background: The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). Aims: The present study is a 3-years follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. Methods: This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. Results: After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with ISS stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. Summary/Conclusion: In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.